Receptor tyrosine kinases are large enzymes that span the cell membrane and possess an extracellular binding domain for growth factors, a transmembrane domain, and an intracellular portion that functions as a kinase to phosphorylate a specific tyrosine residue in proteins and hence to influence cell proliferation. Tyrosine kinases may be classified as growth factor receptor (e.g. EGFR, PDGFR, FGFR and erbB2) or non-receptor (e.g. c-src and bcr-abl) kinases. Such kinases may be aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancers such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. Aberrant erbB2 activity has been implicated in breast, ovarian, non-small cell lung, pancreatic, gastric and colon cancers.
The kinase, c-Met, is the prototypic member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) which include Met, Ron and Sea. The antiangiogenic and antiproliferative activity of c-Met becomes a attractive target. The endogenous ligand for c-Met is hepatocyte growth factor (HGF), also known as scatter factor (SF), because of its ability to disrupt colony formation in vitro. HGF is a derived cytokine known to induce activation of the receptor via autophosphorylation resulting in an increase of receptor dependent signaling in normal and neoplastic cells (Sonnenberg et al., J. Cell Biol. 123:223-235, 1993; Matsumato et al, Crit. Rev. Oncog. 3:27-54, 1992; and Stoker et al., Nature 327:239-242, 1987). Anti-HGF antibodies or HGF antagonists also have been shown the inhibition of tumor metastasis.
Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function. Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma. Tumor angiogenesis, the formation of new blood vessels and their permeability is primarily regulated by (tumor-derived) vascular endothelial growth factor (VEGF), which acts via at least two different receptors: VEGF-R1 (Flt-1); and VEGF-R2 (KDR, Flk-1). The VEGF KDR receptor is highly specific for vascular endothelial cells (Endocr. Rev. 1992, 13, 18; FASEB J. 1999, 13, 9).
The present invention is based on the discovery of compounds that surprisingly inhibit the effect of c-Met and VEGF as well as other signal transduction of kinases, a property of value in the treatment of disease states associated with cell proliferation, angiogenesis and/or other signal transduction pathways, such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune disease, acute inflammation, excessive scar formation and adhesions, lymphoedema, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
It has now been found that compounds of formula I, described below, are a new class of compounds that have advantageous pharmacological properties and inhibit the activity of protein tyrosine kinases, such as c-Met, VEGFr, EGFr, c-kit, PDGF, FGF, SRC, Ron, Tie2 etc. They may also be irreversible inhibitors of protein tyrosine kinases.
Examples of compounds that are similar in structure to those of the present invention are disclosed in the following literatures: WO2005117867, WO 2006108059, WO2007035428, WO2007054831, WO2008041053, WO2008112408, WO2010045095.